Oral tablet for delivery of active ingredients to the gastrointestinal tract

ABSTRACT

The invention relates to an oral tablet for delivery of active ingredients to the gastrointestinal tract comprising a population of particles and an active ingredient to be delivered to the gastrointestinal tract, the population of particles comprising directly compressible (DC) and non-directly compressible (non-DC) sugar alcohol particles, the non-DC particles providing the tablet with a plurality of discrete non-DC areas, and the non-DC areas resulting in induced saliva generation upon mastication of the tablet, wherein the tablet is designed to be masticated and designed to deliver the active ingredient to the gastrointestinal tract as part of the saliva generated upon mastication of the tablet.

FIELD OF THE INVENTION

An oral tablet for delivery of active ingredients to thegastrointestinal tract.

BACKGROUND OF THE INVENTION

Oral tablets for delivery of active pharmaceutical ingredients to thegastrointestinal tract are well-known in the art. A challenge inrelation to such tablets is that many of such tablets are less thanattractive to the user of the tablet. This challenge is significant asusers are more and more focused on taste or oral displeasure and itaffects the effectiveness and the options available for such oraltablets. This challenge is in particular relevant in relation to oraltablets designed for delivery of active pharmaceuticals.

A particular challenge for typical oral tablets may be that swallowingactive ingredient tablets may be difficult for a wide range of people,including children, elderly and e.g. cancer patients with dry mouth.Also, when having difficulty in swallowing, a person may typically keepthe tablet in the mouth for a longer period, resulting in a veryunpleasant taste, which especially for children result in refusal ofswallowing the tablets.

Some solutions may include coating of the tablets to provide a barrierbetween the content of the tablet and the saliva.

Further options include providing the active ingredient in liquidsolution or suspension. One problem is that correct dosing of the activeingredient may be difficult. Another challenge is that actives forgastrointestinal use may typically have a bad taste.

SUMMARY OF THE INVENTION

The invention relates to an oral tablet for delivery of activeingredients to the gastrointestinal tract comprising a population ofparticles and an active ingredient to be delivered to thegastrointestinal tract, the population of particles comprising directlycompressible (DC) and non-directly compressible (non-DC) sugar alcoholparticles, the non-DC particles providing the tablet with a plurality ofdiscrete non-DC areas, and the non-DC areas resulting in induced salivageneration upon mastication of the tablet, wherein the tablet isdesigned to be masticated and designed to deliver the active ingredientto the gastrointestinal tract as part of the saliva generated uponmastication of the tablet.

According to the present invention and active oral tablet mayadvantageously be applied for the purpose of delivery of activeingredients to the gastrointestinal tract. The inventive use of non-DCsugar alcohols for release of active ingredients is attractive in manyways. It is in part very attractive as the active ingredients perceivedvery positive by a user masticating the tablet partly due to extrasalivation but also the mere taste or sweetness sensation obtained dueto the inventive functionality of the non-DC sugar alcohols.

An advantage of the present invention may be that many of the problemsassociated with conventional solutions are solved or may be avoided.Particularly, by means of providing the active ingredient in the oraltablet of the present invention, the active ingredient may be deliveredto the stomach and thus to the gastrointestinal tract without swallowingof the tablet. The induced saliva generation resulting from the non-DCareas facilitate disintegration of the tablet and fast release of theactive ingredient into saliva. Thereby, the user may swallow the activeingredient as fast as possible after intake of the oral tablet. Thus, aconvenient and pleasant delivery of active ingredients to thegastrointestinal tract may be obtained. At the same time, an attractivemouthfeel and taste may be obtained for the user, due to the salivationand fast disintegration of the tablet.

Thus, an advantage of the present invention may be that it provides aconvenient and pleasant delivery of active ingredients to thegastrointestinal tract applicable for persons suffering dysphagia or whoare otherwise unable to swallow pills without discomfort.

Particularly, it may be an advantage that the active ingredient maydisintegrate in the oral cavity and provide a fast release of the activeingredient to the saliva in the oral cavity to allow the user to swallowthe active ingredient as part of saliva. Saliva generation induced bythe tablet may help not only to disintegrate the tablet and release theactive ingredient, but also provide a vehicle for the active ingredientfrom the oral cavity to the gastrointestinal tract for easy swallowing.

Also, in an embodiment of the invention, by providing simultaneousdisintegration of the tablet and release of the active ingredient, anyoff-note taste of the active ingredient may be taste masked due to thenon-DC sugar alcohols. Further, when including flavors in the tablet, arelease of flavors with the active ingredients may provide further tastemasking to allow active ingredients to be released to saliva in the oralcavity and maintain the pleasant mouthfeel and taste.

As an example, an active ingredient, such as caffeine, known for itsnatural bitter taste, may unexpectedly be released in substantialamounts from the oral tablet in the mouth without annoying the user witha distasteful experience. It is thereby possible to obtain a fast effectof such an active ingredient in the gastrointestinal tract as activeingredients with unpleasant taste would usually need to be delivered tothe gastrointestinal tract by means of an oral tablet intended forswallowing.

Thereby side effect as locally concentrated formation of activeingredients, such as acids in the gastrointestinal tract may be avoided.

In the present context, the non-DC sugar alcohol particles areunderstood and defined by the skilled person with reference to theirtypical commercial trade grade.

In an advantageous embodiment of the invention the non-DC sugar alcoholparticles have not been granulated prior to tableting.

Thus, the non-DC sugar alcohol particles are provided as non-granulatedparticles.

These are typically available in a non-DC form of the relevant sugaralcohol as particles which have not been preprocessed by granulationwith other sugar alcohols or binders for the purpose of obtainingso-called direct compressible particles (DC) on the basis of sugaralcohol particles which are by themselves not suitable for directcompression. Such non-DC particles of sugar alcohol may typicallyconsist of the sugar alcohol. Therefore, non-DC sugar alcohol particlesmay be particles consisting of sugar alcohol, which is non-directlycompressible in its pure form. Examples of sugar alcohols which arenon-directly compressible when provided as particles consisting of thesugar alcohol in question include erythritol, xylitol, maltitol,mannitol, lactitol, isomalt, etc.

Therefore, preferred non-DC grades of sugar alcohol may include puresugar alcohol particles.

In an advantageous embodiment of the invention the active ingredient isabsorbable in the gastrointestinal tract.

In an advantageous embodiment of the invention the active ingredient isgastrointestinal agent designed to act in the gastrointestinal tract.

In an advantageous embodiment of the invention at least 25% by weight ofthe active ingredient is absorbed in the gastrointestinal tract.

In an advantageous embodiment of the invention at least 50% by weight ofthe active ingredient is absorbed in the gastrointestinal tract.

In an advantageous embodiment of the invention the active ingredient isa gastrointestinal stimulant.

Examples of GI stimulants include e.g. metoclopramide, cisapride, anddocusate.

In an advantageous embodiment of the invention the active ingredient isa gastrointestinal relaxant.

Examples of GI relaxants include e.g. loperamide and simethicone.

In an advantageous embodiment of the invention the active ingredient isselected from alginate, atenolol, aspirin (acetylsalicylic acid),ampicillin, aminosalicylates, anhydrous citric acid, aspirin, bisacodyl,bismuth subsalicylate, bupropion, caffeine, calcium, calcium carbonate,cetirizine, cimetidine, cisapride, clarithromycin, desloratadine,dexlansoprazole, diphenhydramine HCl, diphenhydramine citrate,dimenhydrinate, docusate erythromycin, dopamine, esomeprazole,famotidine, fexofenadine HCl, guaifenesin, hydrotalcite, ibuprofen,ketoprofen, lactase enzyme, lansoprazole, loratadine, lorcaserin,loperamide, loperamide HCl, magnesium, magnesium carbonate, magnesiumhydroxide, melatonin, methamphetamine HCl, metoclopramide,metronidazole, montelukast, mycostatin, naltrexone, naproxen, naproxensodium, nizatidine, omeprazole, ondansetron, orlistat, pantoprazole,paracetamol (acetaminophen), pectin, phentermine HCl, polypodiumleucotomos, prednisolone, prednisone, progesterone, propranolol,propantheline bromide, pseudoephedrine HCl, phentermine, rabeprazole,ranitidine, roflumilast, scopoloamine butyl hydroxide, simethicone,sodium, sodium bicarbonate, sodium docusate, sumatriptan, testosterone,tetracycline, topiramate, vitamin A, vitamin B, vitamin B12, vitamin C(ascorbic acid), vitamin D, and vitamin E, vitamin K, or any combinationthereof.

The above active ingredients are the active ingredients to be deliveredto the gastrointestinal tract.

In some embodiments, the may comprise further active ingredient, e.g. acombination of two or more active ingredients from the above list, or asa combination of an active ingredient from the above list and anotheractive ingredient.

In an advantageous embodiment of the invention the active ingredient isan analgesic.

Examples of analgesics include e.g. ibuprofen, paracetamol(acetaminophen), ketoprofen, aspirin (acetylsalicylic acid), andnaproxen.

In an advantageous embodiment of the invention the active ingredient isan anesthetic.

In an advantageous embodiment of the invention the active ingredient isan anti-inflammation agent.

In an advantageous embodiment of the invention the active ingredient isa disinfectant.

In an advantageous embodiment of the invention the active ingredient isan antibiotic.

Examples of antibiotics include e.g. ampicillin, erythromycin,tetracycline, clarithromycin, penicillin, and metronidazole.

In an advantageous embodiment of the invention the active ingredient isselected from vitamins, minerals, and supplements (VMS).

Examples of vitamins, minerals, and supplements include e.g. vitamin A,vitamin B, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K.

In an advantageous embodiment of the invention the active ingredient isa hormone.

Examples of hormones include e.g. progesterone, testosterone, andmelatonin.

In an advantageous embodiment of the invention the active ingredient isa steroid.

Examples of steroids include e.g. prednisolone and prednisone.

In an advantageous embodiment of the invention the active ingredient isa proton pump inhibitor.

Examples of proton pump inhibitors include e.g. rabeprazole,pantoprazole, esomeprazole, dexlansoprazole, lansoprazole, andomeprazole.

In an advantageous embodiment of the invention the active ingredient isan antihistamine.

Examples of antihistamines include e.g. cimetidine, ranitidine,famotidine, nizatidine, and desloratadine.

Antihistamines are drugs to treat allergic rhinitis and other allergies.Antihistamines can give release to a person with nasal congestion,sneezing or hives caused by e.g. pollen, dust mites or animal allergy.

In an advantageous embodiment of the invention the active ingredient isa triptan.

Examples of triptans include e.g. sumatriptan.

In an advantageous embodiment of the invention the active ingredient isa xerostomia mitigation agent, such as a xerostomia mitigation agent forcancer patients.

In an advantageous embodiment of the invention the active ingredient isa migraine treatment agent.

In an advantageous embodiment of the invention the active ingredient isan enzyme.

One advantage of enzymes may be that digestion may be accelerated and/orthat intestinal balance is restored or improved.

In an advantageous embodiment of the invention the active ingredient isa gastrointestinal medication.

In this context a gastrointestinal medication is understood as an activeingredient acting in the gastrointestinal tract.

In an advantageous embodiment of the invention the active ingredient isan opioid.

In an advantageous embodiment of the invention the active ingredient isan allergy medication.

In an advantageous embodiment of the invention the tablet is a medicaldevice for alleviating or treating dysphagia by inducing salivageneration.

In an advantageous embodiment of the invention the active ingredient isampicillin.

In an advantageous embodiment of the invention the active ingredient isibuprofen.

In an advantageous embodiment of the invention the active ingredient isondansetron.

In an advantageous embodiment of the invention the active ingredient isparacetamol (acetaminophen).

In an advantageous embodiment of the invention the active ingredient issimethicone.

In an advantageous embodiment of the invention the active ingredient issodium docusate.

In an advantageous embodiment of the invention the tablet is designed torelease the active ingredient in the oral cavity, resulting inabsorption through the oral mucosa of a part of the active ingredient.

In that embodiment, a part of the active ingredient is not absorbedthrough the oral mucosa but is delivered to the gastrointestinal tractas part of saliva generated upon mastication of the tablet. The part ofthe active ingredient delivered to the oral cavity as part of saliva maybe absorbed in the gastrointestinal tract and/or it may act in thegastrointestinal tract as gastrointestinal medication. In this context agastrointestinal medication is understood as an active ingredient actingin the gastrointestinal tract.

In an advantageous embodiment of the invention the tablet comprises acarrier, such as a liposome, for delivering the active ingredient tointestines.

And advantage of the above embodiment may be that sustained release maybe obtained. A further advantage may be that breakdown and/orinactivation in the stomach, caused e.g. by pepsins, may be avoided ordecreased.

In an advantageous embodiment of the invention the tablet comprisesenzymes for enhancing effects in the gastrointestinal tract.

In an advantageous embodiment of the invention the active ingredient isa prodrug to be delivered to intestines.

In an advantageous embodiment of the invention the active ingredient isparacetamol.

In an advantageous embodiment of the invention the active ingredient isibuprofen.

In an advantageous embodiment of the invention the active ingredient isomeprazole.

In an advantageous embodiment of the invention the active ingredient isondansetron.

In an advantageous embodiment of the invention the active ingredient isesomeprazole.

In an advantageous embodiment of the invention the active ingredient isloperamidhydrochlorid.

In an advantageous embodiment of the invention the active ingredient israntidine.

In an advantageous embodiment of the invention the active ingredient ispenicillin.

In an advantageous embodiment of the invention the tablet is designed torelease at least 50% by weight of the active ingredient within 20seconds from onset of mastication.

In an advantageous embodiment of the invention the tablet is designed toprovide fast onset action of the active ingredient.

In an advantageous embodiment of the invention the tablet furthercomprises a saliva production inhibiting agent for controlling salivaproduction.

In an advantageous embodiment of the invention the tablet is designed torelease the active ingredient in the oral cavity for absorption throughthe oral mucosa of a part of the active ingredient, wherein the tabletis designed to deliver a part of the active ingredient to the throat aspart of saliva generated upon mastication of the tablet, and wherein thetablet is designed to deliver a part of the active ingredient to thegastrointestinal tract.

In an advantageous embodiment of the invention the tablet comprisesmeans for sustained release.

In an advantageous embodiment of the invention the active ingredient isat least partly encapsulated.

In an advantageous embodiment of the invention the active ingredient isa prodrug.

In an advantageous embodiment of the invention the part of the activeingredient absorbed through the oral mucosa results in fast onset actionof the active ingredient.

In an advantageous embodiment of the invention the part of the activeingredient delivered to the gastrointestinal tract results in sustainedaction of the active ingredient.

In an advantageous embodiment of the invention the tablet is designed todeliver a part of the active ingredient to the throat as part of salivagenerated upon mastication of the tablet, and wherein the tablet isdesigned to deliver another part of the active ingredient to thegastrointestinal tract.

In an advantageous embodiment of the invention the tablet is designed torelease the active ingredient in the oral cavity for absorption throughthe oral mucosa of a part of the active ingredient, and wherein thetablet is designed to deliver another part of the active ingredient tothe gastrointestinal tract as part of saliva generated upon masticationof the tablet.

In an advantageous embodiment of the invention the part of the activeingredient absorbed through the oral mucosa results in fast onset actionof the active ingredient.

In an advantageous embodiment of the invention the part of the activeingredient delivered to the gastrointestinal tract results in sustainedaction of the active ingredient.

In an advantageous embodiment of the invention the active ingredient isan active pharmaceutical ingredient.

In an advantageous embodiment of the invention the active ingredient isa nutraceutical.

In an advantageous embodiment of the invention said population ofparticles is tableted into a first module and combined with a secondpopulation of particles that is tableted into a second module.

Thus, a synergy between utilization of non-DC sugar alcohol particles asa disintegration promoter due to the lower mechanical strength and alsoas a salivation promoter in combination with a second module, which canprovide additional mechanical strength, thereby acting as a carriermodule. This is especially advantageous when the second population ofparticles contributes to an attractive mouthfeel by a high content of DCsugar alcohols, which also provides mechanical strength to the tablet.

One advantage of the above embodiment may be that the second module mayhave a higher mechanical strength, e.g. by means of a differentcomposition comprising e.g. a very large amount of direct compressibleingredients, such as DC sugar alcohols.

A further advantage of the above embodiment may be that the secondmodule may have a higher loading capacity for e.g. active ingredients,partly due to the higher obtainable mechanical strength achievable bylarge amounts of direct compressible ingredients, such as DC sugaralcohols.

Thus, in the above embodiment said population of particles is tabletedinto a first module, and wherein the tablet further comprises a secondpopulation of particles that is tableted into a second module. The firstmodule may be tableted before the second module, or vice versa. In someembodiments, the tablet may comprise one or more further modules.

According to an embodiment of the invention the active ingredient isincluded in the population of particles.

According to an embodiment of the invention the active ingredient isincluded in the second population of particles.

According to an embodiment of the invention the active pharmaceuticalingredient is included in the population of particles.

According to an embodiment of the invention the active pharmaceuticalingredient is included in the second population of particles.

In an embodiment of the invention the oral tablet comprises at least twomodules. A tablet comprising two or more modules will thus have modulesizes which each are comparable to the volume of the complete tablet.Comparable in the present context means that the modules are notunderstood as small particles and a module should at least be greaterthan 1/20 of the complete tablet volume, preferably greater than 1/10 ofthe complete tablet volume.

The module may typically be gathered from a plurality of compressedparticles and have a weight which is greater than 0.2 gram and less than10 grams.

In an embodiment of the invention a module is defined as a plurality ofparticles being compressed together to form a gathered module ofparticles.

In an embodiment of the invention the oral tablet comprises a pluralityof oral tablet modules. In the present context the application of e.g.two modules are in particular advantageous as the use of non-DC sugaralcohols by nature may result in a more fragile tablet or at least themodule in which the non-DC sugar alcohols are. In other words, non-DCsugar alcohols may be present primarily in one module thereby optimizingthe desired salivation and sensory experience from the module and thetablet as such whereas another module may serve as a support ensuringthat the desired stability and friability of the complete tablet isobtained.

In an embodiment of the invention the plurality of modules areslice-like layers. The term “slice-like” layer is a plain but veryprecise way of to the skilled person how a module may be provided, assuch a layer is a standard structure obtained through conventionaltableting procedures.

According to an embodiment of the invention, the tablet has two modules.Optionally, a coating may be applied around the two modules to form thefinal tablet.

An advantage of using two modules is described above, but it should alsobe noted that this effect may also be obtained when applying layers ofvery different nature. Such application may e.g. include the use of agum module and a non-gum module, where the non-gum modules arecontaining the non-DC sugar alcohol particles. In this way, the non-gumlayer may release the advantageous non-DC sugar alcohols and the gumlayer may both stabilize the tablet as described above but also interactwith the non-DC sugar alcohols during in particular the initial releasefor establishment of a very pleasant and impressing initial chew phase.This includes an increased saliva and moisture experience.

In an embodiment of the invention said population of particles istableted into a first module and combined with a second population ofparticles that is tableted into a second module, where the secondpopulation of particles is different from the first population ofparticles.

In an embodiment of the invention said population of particles istableted into a first module and combined with a second population ofparticles that is tableted into a second module, where the secondpopulation of particles is different from the first population ofparticles, where the second population of particles is free of non-DCsugar alcohols.

In one embodiment, the second population of particles comprises a largeamount of DC sugar alcohols, such as larger amounts than the firstpopulation of particles. For example, the second population of particlesmay comprise at least 30% by weight of DC sugar alcohols, such as atleast 50% by weight of DC sugar alcohols, such as at least 70% by weightof sugar alcohols. In an example embodiment, the second population ofparticles may comprise between 50 and 99.9% by weight of sugar alcohols,such as between 70 and 99% by weight of sugar alcohols.

The amount of DC sugar alcohol may depend on the type and amount ofactive ingredient applied in the tablet.

In an embodiment of the invention the second module is tableted beforethe first module.

In an advantageous embodiment of the invention the non-DC areas areevenly distributed in the tablet or at least one module of the tablet.

One advantage of the above embodiment may be that the even distributionof the non-DC areas promotes an effective disintegration of the moduleupon mastication, e.g. due to lower mechanical strength contributionfrom the non-DC particles, thereby facilitating effective contacting ofthe resulting mastication fragments formed by the mastication withsaliva, again increasing dissolving of the tablet. Also, the evendistribution of the non-DC areas promotes a high number of masticationfragments with non-DC sugar alcohols, which again effectively promotessalivation. Thus, a synergy between utilization of non-DC sugar alcoholparticles as a disintegration promoter due to the lower mechanicalstrength and also as a salivation promoter in combination with the evendistribution to facilitate effect dispersion of mastication fragments inthe oral cavity upon mastication.

In an advantageous embodiment of the invention a series of at least 10of said tablets comprises said non-DC particles in an amount varyingwith a relative standard deviation (RSD) below 10%.

One advantage of the above embodiment may be that uniform product may beobtained having low variation in the amount of non-DC sugar alcoholbetween tablets. Consequently, the functionality provided by non-DCareas in the tablet may provide low variation between tablets.

It is noted that the reference to RSD and a sequence of tabletstypically refers to a tablet series of a production line.

Furthermore, the RSD of the non-DC sugar alcohol between tablets is ameasure of the degree of even distribution of the non-DC areas.Therefore, having an RSD below 10% in a series of at least 10 tabletsindicates an even distribution of the non-DC areas. Having evenlydistributed non-DC areas facilitates a high salivation since the non-DCareas are effectively distributed in the mouth upon mastication and aresulting disintegration of the tablet.

According to an embodiment of the invention, the amount of non-DCparticles between a series of at least 10 of the tablets holds arelative standard deviation (RSD) below 5%.

An advantageous method of dosing non-DC sugar alcohols into acomposition for a large number of tablets has been established, whichfacilitates an exact dosing of the non-DC sugar alcohols in a series oftablets. This means that large-scale production of tablets comprisingnon-DC sugar alcohols is made possible with improved results concerningdistribution of the non-DC areas in the tablets and thereby an improvedRSD between the tablets of a series.

The term RSD as used herein is short for the relative standarddeviation, which within this present field is used to indicate theuniformity in content of non-DC sugar alcohols in a series of tablets.An analysis may be carried out on an array of 10 tablets of a series,wherein the content of the non-DC sugar alcohols in question ismeasured. From these values the RSD may be calculated through thestandard formula of

RSD=(standard deviation of array X)*100%/(average of array X).

In some cases, it may be most convenient to measure RSD of the amount ofnon-DC sugar alcohol particles indirectly. For example, the RSD ofanother ingredient may be used as an indicator for the amount of non-DCsugar alcohol particles, as segregation affects the whole composition ofthe tablet or module in question.

When attempting to obtain a high degree of even distribution of thenon-DC areas, insufficient mixing may lead to uneven distribution, suchas undesirable agglomeration of particles within certain parts of thetablet. Also, even if mixing very thoroughly the ingredients, anundesirable handling of the mixture from the mixing to a tabletingmachine may lead to segregation. For example, smaller particles maytypically segregate to the bottom part of a container, thereby leadingto different particle distributions for different tablets. Particularlywhen the different ingredients have different particle sizes, e.g. ifnon-DC particles have a larger particle size compared to otheringredients, segregation may lead to different contents of non-DC sugaralcohols in different tablets. Yet, another aspect is that even storinga thoroughly mixed composition for too long may lead to segregation.

On the other hand, a measure of having obtained even distribution ofnon-DC areas in at least one module of the tablet may be that a seriesof at least 10 of the tablets holds a relative standard deviation (RSD)below 10% with respect to the non-DC sugar alcohol content.

In is noted that the term segregation as used herein would be known tothe skilled person to mean the separation of a mixture according tosimilarity, typically size.

This may in the present context be a problem when handling a mixturecomprising very different sizes of particles, e.g. in a hopper forholding and feeding the composition via a feeding mechanism to a diecavity.

Particularly, when including an active ingredient in the tablet, havinga low RSD on the content of such active ingredients is highly desirable.

In an advantageous embodiment of the invention the non-DC areas arehomogenously distributed in the tablet or at least one module of thetablet.

One advantage of the above embodiment may be that the homogenousdistribution of the non-DC areas promotes an effective disintegration ofthe module upon mastication, e.g. due to lower mechanical strengthcontribution from the non-DC particles, thereby facilitating effectivecontacting of the resulting mastication fragments formed by themastication with saliva, again increasing dissolving of the tablet.Also, the homogenous distribution of the non-DC areas promotes a highnumber of mastication fragments with non-DC sugar alcohols, which againeffectively promotes salivation. Thus, a synergy between utilization ofnon-DC sugar alcohol particles as a disintegration promoter due to thelower mechanical strength and also as a salivation promoter incombination with the homogenous distribution to facilitate effectdispersion of mastication fragments in the oral cavity upon mastication.

In an advantageous embodiment of the invention the active ingredient isincluded in the second population of particles.

According to an embodiment of the invention, the active ingredient isincluded in the first population of particles.

According to an embodiment of the invention, the active ingredient ispresent in the first population of particles and in the secondpopulation of particles. Thus, in that embodiment the total amount ofactive ingredient may be obtained by combining the first and the secondpopulations of particles.

In an advantageous embodiment of the invention the first and the secondmodules each comprise an amount of the active ingredient, where theamount of active ingredient in the second module is higher than in thefirst module.

In an embodiment of the invention, the active ingredient is comprised inthe second module. Thus, in that embodiment the first module is free ofthe active ingredient.

In an advantageous embodiment of the invention the tablet is a chewabletablet.

In an advantageous embodiment of the invention at least 10% by weight ofsaid population of particles have a particles size below 250 μm, andwherein at least 30% by weight of said population of particles have aparticles size above 500 μm.

According to an embodiment of the invention, the population of particleshave a particle size distribution with a full width at half maximum(FWHM) of at least 100 μm.

Particularly when having a broad particle size distribution of thepopulation of particles, it was surprising to the inventor that evendistribution of the non-DC areas could be accomplished. Typically, whenhaving a broad particle size distribution, such as when having a widthfrom the 10% quantile to the 90% quantile greater than 30% of the meanvalue, associated compositions are considered vulnerable to segregation.However, according to an embodiment of the invention, the non-DC areasare evenly distributed in at least one module of the tablet and may haveamounts of non-DC particles between a series of at least 10 of thetablets holding a relative standard deviation (RSD) below 10%.

According to an embodiment of the invention, the non-DC particles havean average non-DC particle size at least 50 μm larger than an average DCparticle size of the DC particles.

In an advantageous embodiment of the invention the non-DC sugar alcoholparticles are selected from non-DC particles of erythritol, maltitol,xylitol, isomalt, lactitol, mannitol, and combinations thereof.

One advantage of the above embodiment may be that a desirable inducedsaliva generation is obtained.

According to an embodiment of the invention, the non-DC sugar alcoholparticles consist of sugar alcohols selected from erythritol, maltitol,xylitol, isomalt, lactitol, mannitol, and combinations thereof.

In an advantageous embodiment of the invention the non-DC sugar alcoholparticles are selected from non-DC particles of erythritol, maltitol,xylitol, isomalt, and combinations thereof.

One advantage of the above embodiment may be that a desirable inducedsaliva generation is obtained.

In an advantageous embodiment of the invention the non-DC sugar alcoholparticles are selected from non-DC particles of erythritol, maltitol,xylitol, and combinations thereof.

One advantage of the above embodiment may be that a desirable inducedsaliva generation is obtained. Also, when a cooling sensation isdesirable, having non-DC sugar alcohol particles comprising orconsisting of erythritol, xylitol, or combinations thereof advantageous.

In an advantageous embodiment of the invention the non-DC sugar alcoholparticles are non-DC erythritol particles.

One advantage of the above embodiment may be that a desirable inducedsaliva generation is obtained, together with a cooling sensation.

In an advantageous embodiment of the invention the non-DC sugar alcoholparticles are non-DC xylitol particles.

One advantage of the above embodiment may be that a desirable inducedsaliva generation is obtained, together with a cooling sensation.

In an advantageous embodiment of the invention the tablet comprises saidnon-DC sugar alcohol particles in an amount of at least 10% by weight ofthe tablet.

In an advantageous embodiment of the invention said DC sugar alcoholparticles comprises sugar alcohols selected from DC particles ofsorbitol, erythritol, xylitol, lactitol, maltitol, mannitol, isomalt,and combinations thereof.

Sorbitol is an example of a sugar alcohol, which is considered DC grade,when provided as particles consisting of sorbitol, i.e. in its pureform. On the other hand, several other sugar alcohols are considerednon-DC grade if providing them as particles consisting of the specificsugar alcohol. Therefore, such non-DC sugar alcohols are conventionallyprocessed into DC grade sugar alcohols, e.g. by granulating them withe.g. a binder.

Examples of trade grades of DC sugar alcohols include sorbitol particlesprovided as e.g. Neosorb® P 300 DC from Roquette, mannitol particlesprovided as e.g. Pearlitol® 300DC or Pearlitol 200 SD from Roquette,maltitol provided as e.g. SweetPearl® P 300 DC, xylitol provided as e.g.Xylisorb® 200 DC or Xylitab 200 from Dupont.

In an advantageous embodiment of the invention the tablet comprises saidDC sugar alcohol particles in an amount of at least 10% by weight of thetablet.

According to an embodiment of the invention, said population ofparticles comprises DC sugar alcohol particles in an amount of at least10% by weight.

According to an embodiment of the invention, the first module comprisesDC sugar alcohol particles in an amount of at least 10% by weight.

In an embodiment of the invention, the second module comprises DC sugaralcohol particles in an amount of at least 30% by weight of the secondmodule

In an advantageous embodiment of the invention the second modulecomprises DC sugar alcohol particles in an amount of at least 50% byweight of the second module.

In an embodiment of the invention the DC sugar alcohol particles in thesecond module are selected from DC particles of sorbitol, erythritol,xylitol, lactitol, maltitol, mannitol, isomalt, and combinationsthereof.

In an advantageous embodiment of the invention friability of the tabletis less than 3%, such as less than 2%, such as less than 1.5%, whereinfriability is measured according to European Pharmacopoeia 9.1, testmethod 2.9.7. by using a pharmaceutical friability-tester PTF 10E fromPharma Test.

One advantage of the above embodiment may be that a tablet with arelatively high mechanical stability is obtained, while at the same timehaving the desirable mouthfeel of the invention.

According to an embodiment of the invention, friability of the tablet isbetween 0.2% and 3%, such as between 0.2% and 2%, wherein friability ismeasured according to European Pharmacopoeia 9.1, test method 2.9.7. byusing a pharmaceutical friability-tester PTF 10E from Pharma Test.

In an advantageous embodiment of the invention the tablet comprises oneor more binders other than binders forming part of the DC sugar alcoholparticles in an amount of 0.1 to 6% by weight of the tablet.

Suitable binders include Gum Arabic, Methyl Cellulose, Liquid glucose,Tragacanth, Ethyl Cellulose, Gelatin, Hydroxy Propyl Methyl Cellulose(HPMC), Starches, Hydroxy Propyl Cellulose (HPC), Pregelatinized Starch,Sodium Carboxy Methyl Cellulose (NaCMC), Alginic Acid, PolyvinylPyrrolidone (PVP), Maltodextrine (MD); Cellulose, Polyethylene Glycol(PEG), Polyvinyl Alcohols, Polymethacrylates, Copovidone orMicrocrystalline Cellulose (MCC), alone or in combination.

According to an embodiment of the invention, the one or more binderscomprises one or more cellulose binders.

In an embodiment of the invention the one or more binders comprisesmicrocrystalline cellulose (MCC), hydroxypropyl cellulose (HPC) orhydroxypropylmethyl cellulose (HPMC) or any combination thereof.

In an embodiment of the invention the oral tablet compriseshydroxypropyl cellulose (HPC) binder in the amount of 0.1 to 6% byweight of the tablet, such as 0.1 to 5%, such as 0.1 to 4%, such as 0.1to 3%, such as 0.1 to 2% by weight of the tablet.

HPC may be applied as a particular attractive binder. Thus, this binder,when used with non-DC sugar alcohols such as erythritol, exhibits anadvantageous sensory experience when compared to other well-knownbinders. In particular, the user of HPC lower than 4% by weight of thetablet is advantageous, such as 0.1 to 3%, such as 0.1 to 2% by weightof the tablet.

In an embodiment of the invention the non-DC sugar alcohol particles areparticles that are not granulated, and the one or more binders arepresent as separate components in the tablet.

In an embodiment of the invention the non-DC sugar alcohol particles areparticles consisting of the sugar alcohol and the particles are notpre-granulated together with the one or more binders that are present inthe tablet as separate components. It is noted that the use of bindersas particles separate from the non-DC particles does not compromise theadvantageous sensory properties even when applying a firm pressuretableting force, whereas the granulation with the binder to the sugaralcohol clearly reduces the desired sensory properties.

In an advantageous embodiment of the invention the resistance tocrunching of the tablet is greater than 60N, such as greater than 70N,such as greater than 80N, such as greater than 90N, such as greater than100 N, such as greater than 110, such as greater than 130N such asgreater than 150N, wherein the resistance to crunching of the tablet isless than 300N, such as less than 250N, such as less than 200N, whereinthe resistance to crunching is determined according to EuropeanPharmacopoeia 9.1, test method 2.9.8. by using a pharmaceuticalresistance to crunching tester model Pharma Test type PTB 311.

According to an embodiment of the invention, the tablet comprises atleast one module,

the module comprising more than 10% by weight of compressed non-DC sugaralcohol particles, the resistance to crunching of the module beinggreater than 60N, such as greater than 70N, such as greater than 80N,such as greater than 90N such as greater than 100 N,

where the resistance to crunching is determined according to theEuropean Pharmacopoeia 9.1, test method 2.9.8. by using a pharmaceuticalresistance to crunching tester model Pharma Test type PTB 311.

High intensity artificial sweetening agents can also be used alone or incombination with the above sweeteners. Preferred high intensitysweeteners include, but are not limited to sucralose, aspartame, saltsof acesulfame, alitame, saccharin and its salts, cyclamic acid and itssalts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, stevioside(natural intensity sweetener) and the like, alone or in combination. Inorder to provide longer lasting sweetness and flavor perception, it maybe desirable to encapsulate or otherwise control the release of at leasta portion of the artificial sweeteners. Techniques such as wetgranulation, wax granulation, spray drying, spray chilling, fluid bedcoating, conservation, encapsulation in yeast cells and fiber extrusionmay be used to achieve desired release characteristics. Encapsulation ofsweetening agents can also be provided using another tablet componentsuch as a resinous compound.

Usage level of the artificial sweetener will vary considerably and willdepend on factors such as potency of the sweetener, rate of release,desired sweetness of the product, level and type of flavor used and costconsiderations. Thus, the active level of artificial sweetener may varyfrom about 0.001 to about 8% by weight (preferably from about 0.02 toabout 8% by weight). When carriers used for encapsulation are included,the usage level of the encapsulated sweetener will be proportionatelyhigher. Combinations of sugar and/or non-sugar sweeteners may be used inthe formulation.

In an advantageous embodiment of the invention the tablet has a weightratio between said non-DC sugar alcohol particles and said DC sugaralcohol particles, which is between 0.3 and 0.7.

The weight ratio between non-DC sugar alcohol particles and DC sugaralcohol particles have proven significant according to an embodiment ofthe invention in the sense that a relatively high amount of non-DC sugaralcohol particles must be present in order to obtain the mouthfeel andtaste obtained through the invention. However, this taste and mouthfeelalso resides in the DC sugar alcohol particles. An example of such DCsugar alcohol particle is DC grade xylitol, which, together with thenon-DC sugar alcohol particles may provide a mouthfeel which is uniqueand very attractive to test panels.

The weight ratio between non-DC sugar alcohol particles and DC sugaralcohol particles have proven significant as mentioned above in relationto the direct sensation and mouthfeel experienced by the user but is hasmoreover addressed the challenge in relation to mouthfeel when DC sugaralcohol particles crumbles during the initial chew. The mechanicalstability of the tablet is much desired when the tablet is in itsnon-chewed form, but a fast disintegration and dissolving is desirablewhen the tablet is chewed due to the fact that user of the tabletdislike a sandy mouthfeel induced through small hard-pressed crumbles ofDC sugar alcohol. The use of a very high amount of non-DC sugar alcoholparticles will facilitate a perceived fast dissolving and disintegrationof the tablet after the initial chews.

According to an embodiment of the invention the tablet has a weightratio between said non-DC sugar alcohol particles and said DC sugaralcohol particles, which is greater than 0.3, such as greater than 0.4,such as greater than 0.5.

According to an embodiment of the invention the tablet has a weightratio between said non-DC sugar alcohol particles and said DC sugaralcohol particles, which is smaller than 0.7, such as smaller than 0.6,such as smaller than 0.55.

The weight ratio between non-DC sugar alcohol particles and DC sugaralcohol particles is important for the purpose of obtaining anadvantageous taste and mouthfeel. By having an upper limit of thisweight ratio, the chewer will moreover also experience a desirablecrunch sensation when starting masticating the tablet, the crunch beingobtained through the use of substantial amounts of DC sugar alcoholparticles and the non-DC sugar alcohol particles.

According to an embodiment of the invention, the tablet comprises thenon-DC sugar alcohol particles in an amount of greater than 0.3 gram.

According to an embodiment of the invention, the weight of non-DC sugaralcohol particles contained in the tablet is greater than greater than0.4 gram, such as greater than 0.5 gram, such as greater than 0.6 gram,such as greater than 0.7 gram, such as greater than 0.8 gram, such asgreater than 0.9 gram, such as greater than 1.0 gram.

According to a further embodiment of the invention, the amount of non-DCsugar alcohol particles is relatively high. It is in particular highwhen considering that the non-DC sugar alcohol in conventional sense isnot regarded attractive for compression, but the mouthfeel andsalivation perceived by the user is there improved significantly, whencompared to low amounts or the same amounts of DC sugar alcohol.

According to an embodiment of the invention, the tablet comprises thenon-DC sugar alcohol particles in an amount of less than 3.0 gram, suchas less than 2.0 gram, such as less than 1.5 gram.

In an embodiment of the invention wherein the tablet has a weight ofbetween 0.5 and 4.0 grams.

In an advantageous embodiment of the invention saliva generation uponmastication of the tablet is induced compared to a tablet without non-DCsugar alcohol particles.

In an advantageous embodiment of the invention saliva generation uponmastication of the tablet is induced compared to a tablet where thediscrete areas are based on DC sugar alcohol particles.

In an advantageous embodiment of the invention the tablet generates morethan 1.5 mL saliva within 30 seconds from onset of mastication.

According to an embodiment of the invention the discrete non-DC areasinduces saliva generation of more than 2.0 mL saliva within 30 secondsfrom onset of mastication.

According to an embodiment of the invention the discrete non-DC areasinduces saliva generation of more than 3.0 mL saliva within 30 secondsfrom onset of mastication.

In an advantageous embodiment of the invention the tablet generates morethan 1.5 mL saliva within a period from 30 to 90 seconds from onset ofmastication.

According to an embodiment of the invention the discrete non-DC areasinduces saliva generation of more than 2.0 mL saliva within a periodfrom 30 to 90 seconds from onset of mastication.

In an advantageous embodiment of the invention the tablet generates morethan 1.5 mL saliva within a period from 90 to 180 seconds from onset ofmastication.

In an advantageous embodiment of the invention the tablet generates morethan 1.5 mL saliva within a period from 180 to 300 seconds from onset ofmastication.

In an embodiment of the invention, the tablet comprises flavor.

The amount of flavor may e.g. be from 0.1 to about 10% by weight of thetablet, such as 0.1 to about 6% by weight of the tablet.

Usable flavors include almond, almond amaretto, apple, Bavarian cream,black cherry, black sesame seed, blueberry, brown sugar, bubblegum,butterscotch, cappuccino, caramel, caramel cappuccino, cheesecake(graham crust), chili, cinnamon redhots, cotton candy, circus cottoncandy, clove, coconut, coffee, clear coffee, double chocolate, energycow, ginger, glutamate, graham cracker, grape juice, green apple,Hawaiian punch, honey, Jamaican rum, Kentucky bourbon, kiwi, koolada,lemon, lemon lime, tobacco, maple syrup, maraschino cherry, marshmallow,menthol, milk chocolate, mocha, Mountain Dew, peanut butter, pecan,peppermint, raspberry, banana, ripe banana, root beer, RY 4, spearmint,strawberry, sweet cream, sweet tarts, sweetener, toasted almond,tobacco, tobacco blend, vanilla bean ice cream, vanilla cupcake, vanillaswirl, vanillin, waffle, Belgian waffle, watermelon, whipped cream,white chocolate, wintergreen, amaretto, banana cream, black walnut,blackberry, butter, butter rum, cherry, chocolate hazelnut, cinnamonroll, cola, creme de menthe, eggnog, English toffee, guava, lemonade,licorice, maple, mint chocolate chip, orange cream, peach, pina colada,pineapple, plum, pomegranate, pralines and cream, red licorice, saltwater taffy, strawberry banana, strawberry kiwi, tropical punch, tuttifrutti, vanilla, or any combination thereof.

In an advantageous embodiment of the invention the tablet comprisesparticles comprising gum base, and wherein the tablet is designed to bemasticated into a coherent residual containing water-insolublecomponents.

The application of gum may in the present context may invoke a delay ofrelease for active ingredients and this may again promote the buccal andupper throat absorption of active pharmaceutical ingredient when this isreleased from the oral tablet during mastication.

In an advantageous embodiment of the invention the oral tablet containsparticles comprising gum base, and wherein the gum base comprises atleast 5% by weight of elastomer.

The specific use of a relatively high proportion of elastomer in the gumbase may effectively be used for modification of the release of activeingredients in terms of time and amount and the elastomer may alsoprovide robust structure of the tablet facilitating that it is chewedinto a coherent residual containing water-insoluble components. Someactive ingredient may risk invoking disintegration of the residualwhereas an elastomer may increase the coherence and compensate for theaggressive active ingredients.

In an embodiment of the invention the gum base comprises at least 10% byweight of elastomer.

In an embodiment of the invention the gum base comprises at least 15% byweight of elastomer.

In an embodiment of the invention the gum base comprises between 15% and25% by weight of elastomer.

In an embodiment of the invention the gum base comprises between 17% and23% by weight of elastomer.

In an advantageous embodiment of the invention the tablet is free of gumbase.

The invention further relates to an oral tablet for delivery of activeingredients to the gastrointestinal tract comprising a population ofparticles and an active ingredient to be delivered to thegastrointestinal tract, the population of particles comprising directlycompressible (DC) and non-directly compressible (non-DC) sugar alcoholparticles, the tablet being designed to turn into liquid within 20seconds of mastication.

The invention further relates to an oral tablet for delivery of activeingredients to the gastrointestinal tract comprising a population ofparticles and an active ingredient to be delivered to thegastrointestinal tract, the population of particles comprising directlycompressible (DC) and non-directly compressible (non-DC) sugar alcoholparticles, the tablet being designed to dissolve within 20 seconds ofmastication.

According to an advantageous embodiment of the invention the oral tabletaccording to any of the two aforementioned embodiments is composedaccording to the invention or any of its embodiments.

The invention further relates to a method of delivering activeingredients to the gastrointestinal tract, the method comprising thesteps of:

-   -   i) providing an oral tablet comprising a population of particles        and an active ingredient to be delivered to the gastrointestinal        tract, the population of particles comprising directly        compressible (DC) and non-directly compressible (non-DC) sugar        alcohol particles,    -   ii) masticating the tablet and thereby generating saliva in the        oral cavity induced by a plurality of discrete non-DC areas in        the tablet, and    -   iii) delivering the active ingredient to the gastrointestinal        tract as part of the saliva generated upon mastication of the        tablet.

According to an advantageous embodiment of the invention the oral tabletaccording to any of the two aforementioned embodiments is composedaccording to the invention or any of its embodiments. step ii) ofmasticating the tablet involves releasing at least 50% by weight of theactive ingredient within 20 seconds from onset of mastication.

In an advantageous embodiment of the invention the method of theinvention or any of its embodiments involves providing the tablet of theinvention or any of its embodiments.

THE FIGURES

The invention will now be described with reference to the drawings where

FIGS. 1a and 1b shows an embodiment of the invention,

FIGS. 2a and 2b shows a two-module version of an embodiment of theinvention,

FIGS. 3a and 3b shows a three-module version of an embodiment of theinvention,

FIGS. 4 and 5 illustrates embodiments of the invention

FIG. 6 illustrates a two-module version of an embodiment of theinvention and where

FIG. 7 illustrates the short and long-term effect of salivation obtainedthrough different types of non-DC sugar alcohols.

DETAILED DESCRIPTION

As used herein the term “oral tablet” is considered as a tablet for oraluse. Particularly, the oral tablet is considered as formed by tableting,i.e. compression of a particle composition, comprising the mentionedpopulation of particles. Typically, the oral tablet may also be referredto as a tablet. Thus, the oral tablet is considered a compressed tabletformed by a plurality of particles.

In the present context the phrase “population of particles” refers to astatistical population of particles. The population of particles may becharacterized by a number of different parameters, e.g. statisticalparameters such as distribution of particles, average particle size,particle size distribution width, etc. The population of particles mayhave subpopulations, such as DC sugar alcohol particles, non-DC sugaralcohol particles, or in some embodiments particles comprising gum base.The phrasing “population of particles” may in an embodiment of theinvention be provided as a plurality of tableted particles and where thepopulation of particles are tableted in one module or it may refer to apopulation of particles where some of the particles are tableted intoone module and other particles are tableted into another module.

In the present context, the term “non-DC areas” refers to small volumesor spaces formed during tableting from the non-DC particles of non-DCsugar alcohol. Moreover, each of the non-DC areas may be composed of asingle non-DC sugar alcohol particle, or may comprise several non-DCsugar alcohol particles. When the non-DC areas are distinct, i.e. notdiffuse, the non-DC areas may be evenly distributed in the tablet, or atleast one module thereof when the tablet comprises two or more modules.In such embodiments, where the non-DC areas are evenly distributed in inthe tablet, or at least one module thereof, the non-DC areas may thusfacilitate an even saliva generation in the mouth upon mastication.

The term “non-DC sugar alcohol particles” refer to particles ofnon-directly compressible (non-DC) sugar alcohol. It is noted that theterms “non-DC sugar alcohol particles” and “non-DC particles” are usedinterchangeably. In the present context, the non-DC sugar alcoholparticles refer to particles which have not been preprocessed bygranulation with e.g. other sugar alcohols or binders for the purpose ofobtaining so-called direct compressible particles (DC). Thus, non-DCsugar alcohol particles are considered as particles consisting of non-DCsugar alcohol.

The term “DC sugar alcohol particles” refer to particles of directcompressible (DC) sugar alcohol. It is noted that the terms “DC sugaralcohol particles” and “DC particles” are used interchangeably. DC sugaralcohol particles may be obtained e.g. as particles of sugar alcoholshaving DC grade by nature, e.g. sorbitol, or by granulating non-DC sugaralcohol with e.g. other sugar alcohols or binders for the purpose ofobtaining so-called direct compressible particles (DC).

In the present context when the non-DC areas are referred to as“discrete” this signifies that the non-DC sugar alcohols are notcontinuously distributed, but present in the discrete areascorresponding to the discrete nature of the non-DC sugar alcoholparticles.

When referring to induced saliva generation, it is noted that thisinduced saliva generation exceeds any saliva generation without the useof the tablet of the invention. Particularly, in an embodiment theinduced saliva generation exceeds saliva generation when usingconventional tablets without non-DC areas. Then, induced salivageneration is increased over any saliva generation associated withconventional products, e.g. by comparing with a tablet without non-DCsugar alcohol particles, or with a tablet where the discrete areas arebased on DC sugar alcohol particles.

When referring to induced saliva generation, the saliva generation istested using the following method.

Test subject abstain from eating and drinking at least 30 minutes beforeinitiation of any test. Immediately before introducing of the tabletinto the oral cavity, the test subject swallows. The test subjectrefrains from swallowing during the test. Immediately after introducingof the tablet into the oral cavity, the test subject starts masticatingthe tablet at a frequency of 1 chew per second for 20 seconds. Then,saliva and any remains of the tablet is kept in the mouth within chewingfor 10 second. 30 seconds after starting the test, the test subjectdiscards saliva including any tablet fragments into a plastic cup, whichis weighted. Saliva discarded also at 90 seconds after onset ofmastication, at 180 seconds after onset of mastication, at 300 secondsafter onset of mastication, at 420 seconds after onset of mastication,and at 600 seconds after onset of mastication. At all times, the testsubject makes as little movement as possible, and refrains fromswallowing.

As used herein, the term “particle size” refers to the average particlesize as determined according to European Pharmacopoeia 9.1 when usingtest method 2.9.38 particle size distribution estimation by analyticalsieving, unless otherwise specifically is mentioned.

As used herein the term “active ingredient” refers to a substance thatis biologically active and has a physiological effect on the human bodyfor the benefit of the human body or part thereof. Active ingredientsinclude active pharmaceutical ingredients, but also other activesubstances such as nutraceuticals.

In the present context the term “release” refers to the releasedsubstance being liberated from the water-soluble matrix. In someembodiments, the process of releasing a substance corresponds to thesubstance being dissolved in saliva.

As used herein the term “gastrointestinal tract” refers to the part ofthe digestive system starting with the stomach and ending with the anus,including the intestines. Thus, the mouth and esophagus are notconsidered part of the gastrointestinal tract for the purposes of thepresent application.

In the following raw materials will refer to the mixed particles to becompressed into a tablet according to embodiments of the inventionunless otherwise stated.

The following description outlines explanations of how the tablet of theinvention may be produced and further details of what may be added tothe inventive composition.

Typically, the process of manufacture of the inventive tablet may beperformed in a single tablet press, such as a rotary tablet press. Butit may be a benefit under some circumstances to apply a separate tabletpress.

Preferably, the upper punch is convex which gives the upper face of thepressed tablet a concave form.

It should of course be noted that the shape of the punches may varydepending of the desired tablet shape.

In some embodiments of the invention, pressing of the tablets areperformed at a force of 20 to 50 kN.

Important raw materials of the inventive tablet are non-DC sugar alcoholparticles in combination with DC sugar alcohol particles.

The DC sugar alcohol particles refer to sugar alcohols known within theart as being direct compressible (DC).

The non-DC sugar alcohol particles refer to sugar alcohols known withinthe art as being non-directly compressible (DC).

According to a further embodiment of the invention, the applied non-DCsugar alcohol particles are best characterized as being non-directlycompressible (non-DC). The use of non-DC sugar alcohols when compared toconventionally applied direct compressible sugar alcohol (DC) has shownremarkable effects to the user's perception of the delivery vehicle whenchewed. This may partly be due to the somewhat larger size of non-DCsugar alcohol, when compared to DC sugar alcohol, but is may also be aresult of a high content of sugar alcohol in the individual particlesapplied for compression. DC sugar alcohols, which for obvious reasonsare marketed and applied for compression purposes, does not result insuch improved salivation effect and mouthfeel.

It should be noted that the terminology non-DC is easily understoodwithin the field of technology. Suppliers or sugar alcohol providesclear guidance to the user as for the ability for use in relation tocompression of tablets. A non-DC particle in this connection is referredto as a particle which is not expressly recommended by the supplier forcompression. Examples of a non-DC grade of erythritol includes Zerose™erythritol 16952F supplied by Cargill. Further examples of non-DC sugaralcohol particles include non-DC xylitol as Xivia C from Dupont, non-DCisomalt as Isomalt GS from Beneo Paltinit, non-DC mannitol as Pearlitolfrom Roquette, non DC maltitol as Maltisorb. P200 from Roquette.Examples of a direct compressible (DC) grade of erythritol includeZerose™ DC 16966 also supplied by Cargill. Further examples of DC sugaralcohols include sorbitol particles provided as e.g. Neosorb® P 300 DCfrom Roquette, mannitol particles provided as e.g. Pearlitol® 300DC orPearlitol 200 SD from Roquette, maltitol provided as e.g. SweetPearl® P300 DC, xylitol provided as e.g. Xylisorb® 200 DC or Xylitab fromDupont.

Non-direct compressible (non-DC) sugar alcohols may include non-DCgrades of Xylitol, non-DC grades of Erythritol, non-DC grades ofMannitol, non-DC grades of maltitol, non-DC grades of Lactitol, non-DCgrades of Isomalt, or other suitable non-DC grades of sugar alcohols.

Direct compressible (DC) sugar alcohols may include sorbitol which is DCby nature, DC grades of Xylitol, DC grades of Erythritol, DC grades ofMannitol, DC grades of maltitol, DC grades of Lactitol, Isomalt or othersuitable DC grades of sugar alcohols.

The present invention benefits from a synergy between the non-DC sugaralcohol particles and the DC sugar alcohol particles. The DC sugaralcohols may be e.g. sorbitol which is direct compressible by nature orit may be other sugar alcohols which has been preprocessed, e.g. bygranulation with a suitable binder, to obtain particles which whencompressed may encapsulate the non-DC sugar alcohol particles into amechanically stable tablet. At the same time the non-DC sugar alcoholparticles serves as a means for salivation which is both attractive tothe user and also serves for the purpose of dissolving the DC sugaralcohol particles when the tablet is chewed as fast as possible.

According to embodiments of the invention, encapsulated flavors oractive ingredients may be added to the final blend of raw materialsprior to compression.

Different methods of encapsulating flavors or active ingredients, whichmay both refer to flavors or active ingredients mixed into the rawmaterials to be compressed into the chewing gum may e.g. include spraydrying, spray cooling, film coating, coascervation, Double emulsionmethod (Extrusion technology) or prilling.

Materials to be used for the above-mentioned encapsulation methods maye.g. include Gelatine, Wheat protein, Soya protein, Sodium caseinate,Caseine, Gum arabic, Mod. starch, Hydrolyzed starches (maltodextrines),Alginates, Pectin, Carregeenan, Xanthan gum, Locus bean gum, Chitosan,Bees wax, Candelilla wax, Carnauba wax, Hydrogenated vegetable oils,Zein and/or Sucrose.

Preferably, these ingredients should be added subsequent to anysignificant heating or mixing. In other words, the active ingredientsshould preferably be added immediately prior to the compression of thefinal tablet.

If applying the present invention in relation to chewing gum, the addingof active ingredients may be cautiously blended with pre-mixed gum basegranulates and further ingredients such as the ingredients stipulated bythe present claims, immediately prior to the final compression of thetablet.

It is noted that those active ingredients listed in the following, whichare not relevant as active ingredients for delivery to thegastrointestinal tract, are listed only as optional active ingredients.

In one embodiment the tablet according to the invention comprises apharmaceutically, cosmetically or biologically active substance.Examples of such active substances, a comprehensive list of which isfound e.g. in WO 00/25598, which is incorporated herein by reference,include drugs, dietary supplements, antiseptic agents, pH adjustingagents, anti-smoking agents and substances for the care or treatment ofthe oral cavity and the teeth such as hydrogen peroxide and compoundscapable of releasing urea during chewing. Examples of useful activesubstances in the form of antiseptics include salts and derivatives ofguanidine and biguanidine (for instance chlorhexidine diacetate) and thefollowing types of substances with limited water-solubility: quaternaryammonium compounds (e.g. ceramine, chloroxylenol, crystal violet,chloramine), aldehydes (e.g. paraformaldehyde), derivatives ofdequaline, polynoxyline, phenols (e.g. thymol, p-chlorophenol, cresol),hexachlorophene, salicylic anilide compounds, triclosan, halogenes(iodine, iodophores, chloroamine, dichlorocyanuric acid salts), alcohols(3,4 dichlorobenzyl alcohol, benzyl alcohol, phenoxyethanol,phenylethanol), cf. also Martindale, The Extra Pharmacopoeia, 28thedition, pages 547-578; metal salts, complexes and compounds withlimited water-solubility, such as aluminum salts, (for instance aluminumpotassium sulphate AlK(SO4)2, 12H2O) and salts, complexes and compoundsof boron, barium, strontium, iron, calcium, zinc, (zinc acetate, zincchloride, zinc gluconate), copper (copper chloride, copper sulphate),lead, silver, magnesium, sodium, potassium, lithium, molybdenum,vanadium should be included; other compositions for the care of mouthand teeth: for instance; salts, complexes and compounds containingfluorine (such as sodium fluoride, sodium monofluorophosphate,aminofluorides, stannous fluoride), phosphates, carbonates and selenium.Further active substances can be found in J. Dent. Res. Vol. 28 No. 2,pages 160-171, 1949.

Examples of active substances in the form of agents adjusting the pH inthe oral cavity include: acids, such as adipic acid, succinic acid,fumaric acid, or salts thereof or salts of citric acid, tartaric acid,malic acid, acetic acid, lactic acid, phosphoric acid and glutaric acidand acceptable bases, such as carbonates, hydrogen carbonates,phosphates, sulphates or oxides of sodium, potassium, ammonium,magnesium or calcium, especially magnesium and calcium.

Active ingredients may comprise the below mentioned compounds orderivates thereof but are not limited thereto: Acetaminophen,Acetylsalicylic acid, Buprenorphine, Bromhexin, Celcoxib, Codeine,Diphenhydramin, Diclofenac, Etoricoxib, Ibuprofen, Indometacin,Ketoprofen, Lumiracoxib, Morphine, Naproxen, Oxycodon, Parecoxib,Piroxicam, Pseudoefedrin, Rofecoxib, Tenoxicam, Tramadol, Valdecoxib,Calciumcarbonat, Magaldrate, Disulfiram, Bupropion, Nicotine,Azithromycin, Clarithromycin, Clotrimazole, Erythromycin, Tetracycline,Granisetron, Ondansetron, Prometazin, Tropisetron, Brompheniramine,Ceterizin, leco-Ceterizin, Chlorcyclizine, Chlorpheniramin,Chlorpheniramin, Difenhydramine, Doxylamine, Fenofenadin, Guaifenesin,Loratidin, des-Loratidin, Phenyltoloxamine, Promethazin, Pyridamine,Terfenadin, Troxerutin, Methyldopa, Methylphenidate, Benzalcon.Chloride, Benzeth. Chloride, Cetylpyrid. Chloride, Chlorhexidine,Ecabet-sodium, Haloperidol, Allopurinol, Colchinine, Theophylline,Propanolol, Prednisolone, Prednisone, Fluoride, Urea, Actot,Glibenclamide, Glipizide, Metformin, Miglitol, Repaglinide,Rosiglitazone, Apomorfin, Cialis, Sildenafil, Vardenafil, Diphenoxylate,Simethicone, Cimetidine, Famotidine, Ranitidine, Ratinidine, cetrizin,Loratadine, Aspirin, Benzocaine, Dextrometorphan, Phenylpropanolamine,Pseudoephedrine, Cisapride, Domperidone, Metoclopramide, Acyclovir,Dioctylsulfosucc, Phenolphtalein, Almotriptan, Eletriptan, Ergotamine,Migea, Naratriptan, Rizatriptan, Sumatriptan, Zolmitriptan, Aluminumsalts, Calcium salts, Ferro salts, Ag-salts, Zinc-salts, Amphotericin B,Chlorhexidine, Miconazole, Triamcinolonacetonid, Melatonine,Phenobarbitol, Caffeine, Benzodiazepiner, Hydroxyzine, Meprobamate,Phenothiazine, Buclizine, Brometazine, Cinnarizine, Cyclizine,Difenhydramine, Dimenhydrinate, Buflomedil, Amphetamine, Caffeine,Ephedrine, Orlistat, Phenylephedrine, Phenylpropanolamin,Pseudoephedrine, Sibutramin, Ketoconazole, Nitroglycerin, Nystatin,Progesterone, Testosterone, Vitamin B12, Vitamin C, Vitamin A, VitaminD, Vitamin E, Pilocarpin, Aluminumaminoacetat, Cimetidine, Esomeprazole,Famotidine, Lansoprazole, Magnesiumoxide, Nizatide and or Ratinidine.

The invention is suitable for increased or accelerated release of activeagents selected among the group of dietary supplements, oral and dentalcompositions, antiseptic agents, pH adjusting agents, anti-smokingagents, sweeteners, flavorings, aroma agents or drugs. Some of thosewill be described below.

The active agents to be used in connection with the present inventionmay be any substance desired to be released from the tablet. The activeagents, for which a controlled and/or accelerated rate of release isdesired, are primarily substances with a limited water-solubility,typically below 10 g/100 mL inclusive of substances which are totallywater-insoluble. Examples are medicines, dietary supplements, oralcompositions, anti-smoking agents, highly potent sweeteners, pHadjusting agents, flavorings etc.

Other active ingredients are, for instance, paracetamol, benzocaine,cinnarizine, menthol, carvone, caffeine, chlorhexidine-di-acetate,cyclizine hydrochloride, 1,8-cineol, nandrolone, miconazole, mystatine,sodium fluoride, nicotine, cetylpyridinium chloride, other quaternaryammonium compounds, vitamin E, vitamin A, vitamin D, glibenclamide orderivatives thereof, progesterone, acetylsalicylic acid, dimenhydrinate,cyclizine, metronidazole, sodium hydrogen carbonate, the activecomponents from ginkgo, the active components from propolis, the activecomponents from ginseng, methadone, oil of peppermint, salicylamide,hydrocortisone or astemizole.

Examples of active agents in the form of dietary supplements are forinstance salts and compounds having the nutritive effect of vitamin B2(riboflavin), B12, folinic acid, folic acid, niacine, biotine, poorlysoluble glycerophosphates, amino acids, the vitamins A, D, E and K,minerals in the form of salts, complexes and compounds containingcalcium, phosphorus, magnesium, iron, zinc, copper, iodine, manganese,chromium, selenium, molybdenum, potassium, sodium or cobalt.

Furthermore, reference is made to lists of nutritionists accepted by theauthorities in different countries such as for instance US code ofFederal Regulations, Title 21, Section 182.5013.182 5997 and182.8013-182.8997.

Examples of active agents in the form of antiseptics are for instancesalts and compounds of guanidine and biguanidine (for instancechlorhexidine diacetate) and the following types of substances withlimited water-solubility: quaternary ammonium compounds (for instanceceramine, chloroxylenol, crystal violet, chloramine), aldehydes (forinstance paraformaldehyde), compounds of dequaline, polynoxyline,phenols (for instance thymol, para chlorophenol, cresol)hexachlorophene, salicylic anilide compounds, triclosan, halogenes(iodine, iodophores, chloroamine, dichlorocyanuric acid salts), alcohols(3,4 dichlorobenzyl alcohol, benzyl alcohol, phenoxyethanol,phenylethanol), cf. furthermore Martindale, The Extra Pharmacopoeia,28th edition, pages 547-578; metal salts, complexes and compounds withlimited water-solubility, such as aluminum salts, (for instance aluminumpotassium sulphate AlK(SO4)2,12H2O) and furthermore salts, complexes andcompounds of boron, barium, strontium, iron, calcium, zinc, (zincacetate, zinc chloride, zinc gluconate), copper (copper chloride, coppersulfate), lead, silver, magnesium, sodium, potassium, lithium,molybdenum, vanadium should be included; other compositions for the careof mouth and teeth: for instance; salts, complexes and compoundscontaining fluorine (such as sodium fluoride, sodiummonofluorophosphate,amino fluorides, stannous fluoride), phosphates, carbonates andselenium.

Cf furthermore J. Dent. Res. Vol. 28 No. 2, pages 160-171, 1949, whereina wide range of tested compounds is mentioned.

Examples of active agents in the form of agents adjusting the pH in theoral cavity include for instance: acceptable acids, such as adipic acid,succinic acid, fumaric acid, or salts thereof or salts of citric acid,tartaric acid, malic acid, acetic acid, lactic acid, phosphoric acid andglutaric acid and acceptable bases, such as carbonates, hydrogencarbonates, phosphates, sulfates or oxides of sodium, potassium,ammonium, magnesium or calcium, especially magnesium and calcium.

Examples of active agents in the form of anti-smoking agents include forinstance: nicotine, tobacco powder or silver salts, for instance silveracetate, silver carbonate and silver nitrate.

Further examples of active agents are medicines of any type.

Examples of active agents in the form of medicines include caffeine,salicylic acid, salicyl amide and related substances (acetylsalicylicacid, choline salicylate, magnesium salicylate, sodium salicylate),paracetamol, salts of pentazocine (pentazocine hydrochloride andpentazocinelactate), buprenorphine hydrochloride, codeine hydrochlorideand codeine phosphate, morphine and morphine salts (hydrochloride,sulfate, tartrate), methadone hydrochloride, ketobemidone and salts ofketobemidone (hydrochloride), beta-blockers, (propranolol), calciumantagonists, verapamil hydrochloride, nifedinpine as well as suitablesubstances and salts thereof mentioned in Pharm. Int., Nov. 85, pages267-271, Barney H. Hunter and Robert L. Talbert, nitroglycerine,erythrityl tetranitrate, strychnine and salts thereof, lidocaine,tetracaine hydrochloride, etorphine hydrochloride, atropine, insulin,enzymes (for instance papain, trypsin, amyloglucosidase, glucoseoxidase,streptokinase, streptodornase, dextranase, alpha amylase), polypeptides(oxytocin, gonadorelin, (LH.RH), desmopressin acetate (DDAVP),isoxsuprine hydrochloride, ergotamine compounds, chloroquine (phosphate,sulfate), isosorbide, demoxytocin, heparin.

Other active ingredients include beta-lupeol, Letigen®, Sildenafilcitrate and derivatives thereof.

Further examples of active ingredients include dental products includingCarbamide, CPP Caseine Phospho Peptide; Chlorhexidine, Chlorhexidine diacetate, Chlorhexidine Chloride, Chlorhexidine di gluconate, Hexetedine,Strontium chloride, Potassium Chloride, Sodium bicarbonate, Sodiumcarbonate, Fluor containing ingredients, Fluorides, Sodium fluoride,Aluminum fluoride.

Further examples of active ingredients include Ammonium fluoride,Calcium fluoride, Stannous fluoride, Other fluor containing ingredientsAmmonium fluorosilicate, Potassium fluorosilicate, Sodiumfluorosilicate, Ammonium monofluorphosphate, Calcium monofluorphosphate,Potassium monofluorphosphate, Sodium monofluorphosphate, OctadecentylAmmonium fluoride, Stearyl Trihydroxyethyl PropylenediamineDihydrofluoride

Further examples of active ingredients include vitamins. Vitaminsinclude A, B1, B2, B6, B12, Folinic acid, Folic acid, niacin,Pantothenic acid, biotine, C, D, E, K. Minerals include Calcium,phosphor, magnesium, iron, Zinc, Copper, Iod, Mangan, Crom, Selene,Molybden. Other active ingredients include:

Q10®, enzymes. Natural drugs including Ginkgo Biloba, ginger, and fishoil.

Further examples of active ingredients include migraine drugs such asSerotonin antagonists: Sumatriptan, Zolmitriptan, Naratriptan,Rizatriptan, Eletriptan; nausea drugs such as Cyclizin, Cinnarizin,Dimenhydramin, Difenhydrinat; hay fever drugs such as Cetrizin,Loratidin, pain relief drugs such as Buprenorfin, Tramadol, oral diseasedrugs such as Miconazol, Amphotericin B, Triamcinolonaceton; and thedrugs Cisaprid, Domperidon, Metoclopramid. In a preferred embodiment theinvention relates to the release of Nicotine and its salts.

In an advantageous embodiment of the invention the active ingredient isselected from active ingredients for the throat selected fromacetylcysteine, ambroxol, amylmetacresol, benzocaine, bisacodyl, bismuthsubsalicylate, bromhexine, cetirizine, cetylpyridinium, chlorhexidine,dextromethorphan hydrobromide, 2,4-dichlorobenzyl alcohol, doxylaminesuccinate, eucalyptus oil, flurbiprofen, glycerin, hexylresorcinol,lidocaine, menthol, myrrh, paracetamol, pectin, peppermint oil, phenol,phenylephrine, povidone-iodine, pseudoephedrine, ranitidine,simethicone, sodium docusate, spearmint, zinc, or any combinationthereof; active ingredients for the gastrointestinal tract selected fromalginate, atenolol, aspirin (acetylsalicylic acid), ampicillin,aminosalicylates, anhydrous citric acid, aspirin, bisacodyl, bismuthsubsalicylate, bupropion, caffeine, calcium, calcium carbonate,cetirizine, cimetidine, cisapride, clarithromycin, desloratadine,dexlansoprazole, diphenhydramine HCl, diphenhydramine citrate,dimenhydrinate, docusate erythromycin, dopamine, esomeprazole,famotidine, fexofenadine HCl, guaifenesin, hydrotalcite, ibuprofen,ketoprofen, lactase enzyme, lansoprazole, loratadine, lorcaserin,loperamide, loperamide HCl, magnesium, magnesium carbonate, magnesiumhydroxide, melatonin, methamphetamine HCl, metoclopramide,metronidazole, montelukast, mycostatin, naltrexone, naproxen, naproxensodium, nizatidine, omeprazole, ondansetron, orlistat, pantoprazole,paracetamol (acetaminophen), pectin, phentermine HCl, polypodiumleucotomos, prednisolone, prednisone, progesterone, propranolol,propantheline bromide, pseudoephedrine HCl, phentermine, rabeprazole,ranitidine, roflumilast, scopoloamine butyl hydroxide, simethicone,sodium, sodium bicarbonate, sodium docusate, sumatriptan, testosterone,tetracycline, topiramate, vitamin A, vitamin B, vitamin B12, vitamin C(ascorbic acid), vitamin D, and vitamin E, vitamin K, or any combinationthereof, and active ingredients for buccal absorption selected fromatenolol, baclofen, caffeine, carvedilol, chlorpheniramine,chlorpheniramine maleate, fluticasone propionate, maleate, desmopressin,diltiazem hydrochloride, doxylamine succinate, mycostatin, nicotine,nifedipine, nitroglycerin, omeprazole, ondansetron, oxymetazoline HCl,oxytocin, phenylephrine, piroxicam, prednisone, propranolol, salbutamolsulphate, scopoloamine butyl hydroxide, sumatriptan,triamcinolonacetonid, and any combination thereof.

In a further embodiment, the sucrose fatty acid esters may also beutilized for increased release of sweeteners including for instance theso-called highly potent sweeteners, such as for instance saccharin,cyclamate, aspartame, thaumatin, dihydrocalcones, stevioside,glycyrrhizin or salts or compounds thereof. For increased released ofsweetener, the sucrose fatty acids preferable have a content ofpalmitate of at least 40% such as at least 50%.

When including gum base in the formulation sugar alcohols typicallyconstitute from about 5 to about 95% by weight of the tablet, moretypically about 20 to about 80% by weight such as 30 to 70% or 30 to 60%by weight of the tablet.

In an embodiment of the invention, the tablet further comprises, besidethe already described sugar alcohols, materials selected from the groupconsisting of bulk sweeteners, flavors, dry-binders, tableting aids,anti-caking agents, emulsifiers, antioxidants, enhancers, absorptionenhancers, buffers, high intensity sweeteners, softeners, colors, or anycombination thereof.

Suitable sugar alcohols typically constitute from about 40 to about99.9% by weight of the tablet, such as about 80 to about 99% by weightof the tablet.

High intensity artificial sweetening agents can also be used alone or incombination with the above sweeteners. Preferred high intensitysweeteners include, but are not limited to sucralose, aspartame, saltsof acesulfame, alitame, saccharin and its salts, cyclamic acid and itssalts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, stevioside(natural intensity sweetener) and the like, alone or in combination. Inorder to provide longer lasting sweetness and flavor perception, it maybe desirable to encapsulate or otherwise control the release of at leasta portion of the artificial sweeteners. Techniques such as wetgranulation, wax granulation, spray drying, spray chilling, fluid bedcoating, conservation, encapsulation in yeast cells and fiber extrusionmay be used to achieve desired release characteristics. Encapsulation ofsweetening agents can also be provided using another tablet componentsuch as a resinous compound.

Usage level of the artificial sweetener will vary considerably and willdepend on factors such as potency of the sweetener, rate of release,desired sweetness of the product, level and type of flavor used and costconsiderations. Thus, the active level of artificial sweetener may varyfrom about 0.001 to about 8% by weight (preferably from about 0.02 toabout 8% by weight). When carriers used for encapsulation are included,the usage level of the encapsulated sweetener will be proportionatelyhigher. Combinations of sugar and/or non-sugar sweeteners may be used inthe tablet formulation.

A tablet according to the invention may, if desired, include one or morefillers/texturisers including as examples, magnesium and calciumcarbonate, sodium sulphate, ground limestone, silicate compounds such asmagnesium and aluminum silicate, kaolin and clay, aluminum oxide,silicium oxide, talc, titanium oxide, mono-, di- and tri-calciumphosphates, cellulose polymers and combinations thereof.

FIGS. 1a and 1b illustrates an embodiment of an oral tablet 10 accordingto an embodiment of the invention. FIG. 1a shows the oral tablet fromthe side and FIG. 1b shows the tablet from above.

The composition and the way the tablet is or can be made is describedelsewhere in the application and details regarding the structure andfunctioning of this tablet 10 is also indicated and explained furtherwith reference to FIG. 4 and FIG. 5.

FIGS. 2a and 2b illustrates a two-module version of an oral tabletaccording to an embodiment of the invention. FIG. 2a shows the oraltablet from the side and FIG. 2b shows the tablet from above.

The composition and the way the tablet is made is described elsewhere inthe application.

Details regarding the structure and functioning of this tablet 10 isalso indicated and explained further with reference to FIGS. 4, 5 and 6.

The intention with this illustration is to give an example of a physicalform, which may be applicable within the scope of the invention. Theintention is also to illustrate how the term “a module” is understoodand applied throughout the description, i.e. that a module is referringto a population of a plurality particles and the particles have beentableted together to form a module. The term module is applied toindicate that one module comprises one population of tableted particlesand another module comprises another population of tabled particles. Apopulation of particles in the present context is thus understood torefer to a plurality of particles. A singular particle is thus of coursenot understood as a module.

Modules are typically, but not necessarily, distinguishable by the humaneye, in particular if the applied compounds in the different modules areformed by differently colored population of particles or mixtures ofparticles.

The oral tablet 20 comprises an upper module 21 and a lower module 22.The modules, here in the shapes of layers, are thus physically distinctand each comprises a population of particles which has been tableted.The population of the different modules, 21 and 22, may typically bedifferent for many purposes. Examples include use for visual conception,for mechanical purposes e.g. providing strength, for medical purposes,and of course also for maximizing the desired effect of non-DC sugaralcohol contained in the tablet.

In a preferred embodiment, most of the applied non-DC sugar alcohol(s)is comprised in the upper module 21 and the lower module 22 is mostlycomprised of DC-components, i.e. components such as sugar alcohols,fillers, flavors, colors etc. conventionally used for directcompression. In embodiments of the invention, a first module, here thelower module 22 may be regarded and applied as a support modulesupporting another module, here the upper module 21. The benefit of thisdivision in the designing of properties is that the module containingthe non-DC sugar alcohol particles may comprises substantial amounts ofnon-DC sugar alcohol particles even in spite of the fact that themodules own mechanical strength is substantially weakened, as thesupporting modules structural strength may be designed to ensure thatthe overall structural strength of the tablet is sufficient to obtainthe desired friability and tablet appearance. This multi-modular designapproach is of even more interest as the tablets designed according tothis principle benefits, in terms of disintegration and dissolving ofthe tablet matrix during mastication of the tablet, from the increasedsalivation effect obtained from the applied high content of non-DC sugaralcohol particles in the relatively weak module.

FIGS. 3a and 3b illustrates a three-module version of an oral tablet 30according to an embodiment of the invention. FIG. 3a shows the oraltablet 30 from the side and FIG. 3b shows the tablet from above.

The illustrated tablet 30 comprises an upper module 31, and intermediatemodule 33 and a lower module 32.

The upper module 31 may, as explained in relation to the upper module ofFIGS. 2a and 2b , be formed by a population of particles comprising aneffective amount of non-DC sugar alcohol particles. The intermediatelayer may comprise further non-DC sugar alcohol particles and or adesired active ingredient.

The lower module 32 may comprise substantial amounts of DC-particlessuch as sugar alcohol(s), fillers, some binder and other relevantingredients enabling the lower module 32 to form a structural supportfor at least the upper module 31.

FIG. 4 illustrates a part 40 of a cross-section of one of the oraltablets in FIG. 1-3. The part of the oral tablet, illustrated in FIG. 4may thus correspond to a view of a part of the upper layers 21 or 31 ora part of the tablet 1.

Such part 40 of a tablet may within the scope of the invention compriseat least two different types of particles, namely non-DC sugar alcoholparticles 41 and DC-particles 42. Preferred but non-limiting non-DCsugar alcohols are non-DC erythritol and non-DC xylitol as these non-DCsugar alcohols have shown effective to obtain the desired effect. Theillustrated non-DC particles 41, although indicated on the figures withthe same graphical expression may of course comprise non-DC sugaralcohol particles of the same type, but also comprise a mixture of twoor more non-DC sugar alcohol particles.

The particles are evenly distributed amongst a plurality of DC particles42 within the specified module. The DC particles 42, although indicatedin the figure as same type particles may include different types of DCsugar alcohol particles, flavor particles, binders, etc. The intentionwith the figure is to illustrate that the non-DC sugar alcohol particles41 in practice have to be homogenously distributed amongst the DCparticles 42 in the final oral tablet 40. It may not be enough that thenon-DC particles and DC particles are mixed homogenously at some stageduring the preparation of the tableting process. The homogenous mixshould preferably be maintained in the final oral tablet 40 in order topromote the desired effect and to obtain a mechanically stable tablet. Afurther advantageous effect of the evenly distributed non-DC sugaralcohol particles may be obtained through an advantageous and increasedsalivation during mastication of a tablet.

The understanding and conception of the evenly distribution of thenon-DC sugar alcohol particles in the relevant tablet module may inpractical terms be very difficult to define as such definitions are verydifficult to monitor and control during the processing of the tablet butit has been possible to establish an industrial scale process, where themixture containing the substantial amounts of non-DC sugar alcohol(s)may be established all the way through the process into the finaltablet. Such process may e.g. be validated by test manufacturing of asequence of tablets where the variation of the non-DC sugar alcoholcontent of the manufactured tablets are determined.

It is noted that the non-DC particles 41 forms small sub-areas or subspaces in the final oral tablet or the relevant module of the finaltablet, e.g. the upper modules 21 and 31. These sub-areas are elsewherein the present application referred to as discrete non-DC areas and maybe formed by single non-DC particles or very small groups of thesenon-DC particles. These discrete non-DC areas are thus intended to becontained within a matrix formed by DC-sugar alcohol particles or otherDC-particles.

The non-DC areas, in the present embodiment, the non-DC sugar alcoholparticles 41 are thus included in substantial amounts in the tablet andfrom a mechanical perspective supported and contained by theDC-particles 42 and together forming a matrix which, when chewed, maybring the non-DC sugar alcohol particles 41 into contact with the oralcavity and promote salivation. The promoted salivation, together withrelatively weak mechanical structure of the module or tablet comprisingthe non-DC sugar alcohol particles induces a fast breakup of the tabletand thereby pushes the non-DC particles into contact with the oralcavity in a way which is completely different from compressed tabletsmade from DC-sugar alcohol particles, such as granulated erythritol orxylitol.

The non-DC areas may thus result in induced saliva generation uponmastication of the tablet and also induce and promote a very fast andpleasant dissolving of the tablet matrix when compared to conventionalcompressed tablets.

Active ingredients may be present as both DC and non-DC particles aslong as the active ingredient as such does not interfere significantwith other compounds. If the active ingredients are non-DC particles,the amount should be kept low enough to ensure the mechanical stabilityof the tablet or modules or alternatively compensated by relevantDC-particles or binders. It should be noted that such a compensationshould be carefully considered as this compensation may both compromisesalivation effect and texture/mouthfeel during mastication.

FIG. 5 illustrates a part of a cross-section of one of the oral tabletsin FIG. 1-3. The part of the oral tablet, illustrated in FIG. 5 may thuscorrespond a view of a part of the upper modules 21 or 31 or the tablet1.

In terms of components applied, the tablet part illustrated in FIG. 5may largely correspond to the above-described embodiment of FIG. 4, butnow the tablet part comprises larger sized non-DC particles 51containing in a compression of particles of DC particles 52.

The intention with the present FIG. 5 is merely to indicate that inparticular the non-DC sugar alcohol particles may be larger in size thanthe DC particles and it is also noted in this context that the use oflarger sized non-DC sugar alcohol particles may indeed increase theobtained salivation or the desired effect.

FIG. 6 illustrates a particular transition in a tablet 60 with twoadjacent modules according to an embodiment of the invention. Thepresently illustrated part of such tablet may e.g. refer to thetransition between the modules 21 and 22 of the tablet 20 as seen inFIG. 2a . The tablet 60 comprises non-DC sugar alcohol particles 61 andDC particles 62 in one module and another module comprising DC particles63. The understanding of a module is here easily conceivable as thepopulation of non-DC sugar alcohol particles 61 and DC particles 62forms one module and the population of DC particles 63 forms anothermodule. Often, the compositions of the DC sugar alcohol particles 62 andthe DC sugar alcohol particles 63 may be different, depending on thespecific circumstances.

Again, in relation to FIG. 5 and FIG. 6, active ingredients may bepresent as both DC and non-DC particles as long as the active ingredientas such does not interfere significant with other compounds. If theactive ingredients are non-DC particles, the amount should be kept lowenough to ensure the mechanical stability of the tablet or modules oralternatively compensated by relevant DC-particles or binders. It shouldbe noted that such a compensation should be carefully considered as thismay compensation may both compromise salivation effect andtexture/mouthfeel during mastication.

Particles comprising gum base, may also be present both as non-DC and DCparticles, although DC-particles comprising gum base are highlypreferred over non-DC gum base-containing particles. When applyingparticles comprising gum base, these particles are preferably but notnecessarily included in a supporting module as DC particles 63 e.g. withmixed with sugar alcohol particles 63 as illustrated in FIG. 6.

The above illustrated modules are all designed as layers. It is stressedthat other shapes of modules may be applicable within the scope of theinvention. Non-limiting examples are modules having a sphere shape,diamond shape, oval shape, cone shape, etc. All the relevant shapes mustof course be adapted to fit the tableting process according to knownmeasures within the art.

EXAMPLES Examples 1-18. Preparation of Two-Layer Tablets

TABLE 1A Oral tablet compositions for bi-layer tablets containing GIactive ingredients. Amount are given in wt-% of the respective layer oftablet. Ex. Ex. Ex. Ex. Ex. Ex. 1 2 3 4 5 6 First layer (wt %) Non DCErythritol 50 50 50 50 50 50 DC Isomalt 43.75 43.75 43.75 43.75 43.7543.75 Flavor 4 4 4 4 4 4 HIS 0.25 0.25 0.25 0.25 0.25 0.25 MagnesiumStearate 1 1 1 1 1 1 Binder HPC 1 1 1 1 1 1 Second layer (wt %) DCMaltitol 92.75 74.75 93.75 44.75 94.55 74.75 DC Xylitol DC IsomaltFlavor 4 4 4 4 4 4 HIS 0.25 0.25 0.25 0.25 0.25 0.25 Magnesium Stearate1 1 1 1 1 1 ACT Omeprazole 2 Ibuprofen 20 Ondansetron 1 Paracetamol 50(Acetaminophen) Loperamidhydrochlorid 0.2 Rantidine 20

TABLE 1B Oral tablet compositions for bi-layer tablets containing GIactive ingredients. Amount are given in wt-% of the respective layer oftablet. Ex. Ex. Ex. Ex. Ex. Ex. 7 8 9 10 11 12 First layer (wt %) Non DCErythritol 50 50 50 50 50 50 DC Isomalt 43.75 43.75 43.75 43.75 43.7543.75 Flavor 4 4 4 4 4 4 HIS 0.25 0.25 0.25 0.25 0.25 0.25 MagnesiumStearate 1 1 1 1 1 1 Binder HPC 1 1 1 1 1 1 Second layer (wt %) DCMaltitol DC Xylitol 92.75 74.75 93.75 44.75 94.55 74.75 DC IsomaltFlavor 4 4 4 4 4 4 HIS 0.25 0.25 0.25 0.25 0.25 0.25 Magnesium Stearate1 1 1 1 1 1 ACT Omeprazole 2 Ibuprofen 20 Ondansetron 1 Paracetamol 50(Acetaminophen) Loperamidhydrochlorid 0.2 Rantidine 20

TABLE 1C Oral tablet compositions for bi-layer tablets containing GIactive ingredients. Amount are given in wt-% of the respective layer oftablet. Ex. Ex. Ex. Ex. Ex. Ex. 13 14 15 16 17 18 First layer (wt %) NonDC Erythritol 50 50 50 50 50 50 DC Isomalt 43.75 43.75 43.75 43.75 43.7543.75 Flavor 4 4 4 4 4 4 HIS 0.25 0.25 0.25 0.25 0.25 0.25 MagnesiumStearate 1 1 1 1 1 1 Binder HPC 1 1 1 1 1 1 Second layer (wt %) DCMaltitol DC Xylitol DC Isomalt 92.75 74.75 93.75 44.75 94.55 74.75Flavor 4 4 4 4 4 4 HIS 0.25 0.25 0.25 0.25 0.25 0.25 Magnesium Stearate1 1 1 1 1 1 ACT Omeprazole 2 Ibuprofen 20 Ondansetron 1 Paracetamol 50(Acetaminophen) Loperamidhydrochlorid 0.2 Rantidine 20

The compositions indicated in the above Tables 1A, 1B and 1C are eachprocessed into corresponding two-layer tablets with compositions asoutlined in examples 1-18.

For each example 1-18 the raw materials are sieved with a 1600 micronsieve and then weighed into the proper amount according to the exampledcompositions of Tables 1A to 1C.

For each layer the weighed amounts are then added to a Turbula mixer ina stainless steel container and blended at 50 rpm for 5 minutes. MgStwas added after 4 minutes of blending.

It is noted that the active ingredient ACT is present in the secondlayer in all examples. It should be noted that the six exemplifiedactive GI ingredients are in no way limiting and it is also noted thatit is possible to administer the active ingredients via the first layer.The shown way of administering the active ingredient via the secondlayer, i.e. the layer not containing the non-DC sugar alcohol,represents a very advantageous design in terms of the desired technicaleffect. It is also noted that each tablet may also contain more than oneactive ingredient and it is also noted that different active ingredientsin that case may be distributed in different layers. It is also notedthat more than two layers may also be applied within the scope of theinvention, and one advantageous design e.g. may include two layers, afirst and a second layer as specified herein but now added with anintermediate layer comprising one of the applied active ingredients. Itshould also be noted that the term layer in relation to the presentembodiment may elsewhere in this application be referred to as a module.In terms of active ingredients, it is noted that some active ingredientsmay advantageously be applied on a tablet which is not multi-modular.

The mixtures are then tableted by means of a Piccola RIVA DC-SC-041-2 ora Fette 3090i.

The applied molds have circular cross sections with diameters of 16 mmand are hollowed to produce tablets, which are concave and/or curved.Evidently, other mold size and shapes may be applied within the scope ofthe invention.

The resulting tablets according to Examples 1-18 are then obtained bytableting with a suitable pressure force.

For each tablet of examples 1-18, the second layer as outlined in theabove table is pressed initially at a first relatively low pressure. Theblended composition of the so-called first layer is then fed to the moldand a final two-layer tablet is then compressed at higher pressure thanthe pressure applied on the first layer, thereby producing finaltwo-layer tablets according to Examples 1-18. It is noted that the finaltwo-layer tablets of examples 1-18 are 1.8 gram tablets and that thefirst layer of the tablets weighs 0.9 and the second layer of thetablets weighs 0.9 gram.

A specification of relevant compounds applied in the examples explainedabove are listed below.

HPC: Hydroxy propyl cellulose. Klucel Nutra D from Ashland

Non DC Erythritol: Zerose 16952 from Cargill

DC Xylitol—Xylitab 200 from Dupont

DC Isomalt—Isomalt DC 101 from Beneo Paltinit

DC Maltitol—Sweetpearl 300 DC from Roquette

The above two-layer Examples 1-18 were evaluated according to mechanicalstrength and the important salivation was evaluated as explained belowwith reference to FIG. 7.

It was noted that the use of DC maltitol, DC Xylitol and DC Isomalt inthe second layer was regarded sufficient and an attractive mean forcarrying the respective active ingredients from a mechanicalperspective, which is important due to the fact that the high load ofnon-DC-sugar alcohol in the first layer will weaken the first layer.

In terms of the salivation effect, it is noted that the swallowabilityis promoted through the use of the non-DC sugar alcohols. To many usersswallowing of an oral tablet containing an active ingredient isdifficult or impossible and the intended administration of the activeingredient in question is considered extremely difficult. It is alsonoted that fast melting tablets are often equally difficult andunpleasant for a user. The present chewable tablets are increasing theability of a user to get the benefit of the active ingredient as theinventive oral tablet promotes salivation to a degree that makes theuser able to accept swallowing the active ingredient when the tablet ismasticated and the active ingredient is in the mouth. The salivation ineffect promotes taste masking or other type of masking of unpleasantmouthfeel. The motivation for swallowing the masticated oral tablet isgreatly increased by the use of the non-DC sugar alcohol, and inparticular when the applied main source of non-DC sugar alcohol iserythritol.

FIG. 7 illustrates a measuring of the salivation effect related to theabove-mentioned Example 7 in different variants, where different non-DCsugar alcohols have been applied in a tablet according to Example 7without an active ingredient (that is: omeprazole is omitted) and wherethe non-DC sugar alcohol has been exchanged with alternatives to thenon-DC erythritol applied in Example 7. Sorbitol is applied as areference, representative DC sugar alcohol.

ISX1 refers to a non-DC xylitol variant of Example 7 with same amount ofnon-DC sugar alcohol,

ISX2 refers to a non-granulated sorbitol variant of Example 7 with sameamount of non-DC sugar alcohol,

ISX3 refers to a non-DC isomalt variant of Example 7 with same amount ofnon-DC sugar alcohol,

ISX4 refers to a non-DC erythritol corresponding to Example 7,

ISX5 refers to a non-DC mannitol variant of Example 7 with same amountof non-DC sugar alcohol and

ISX6 refers to a non-DC maltitol variant of Example 7 with same amountof non-DC sugar alcohol.

The saliva generation as measured with reference to FIG. 7 and theassociated examples is defined in the description as a definition withreference to the measuring method.

The results of the measured saliva generation are illustrated in FIG. 7,where saliva generation in measured in grams as a function of time(minutes).

It is noted that the saliva generation from all non-DC sugar alcoholsare impressive in the beginning, but it is also noted that salivageneration over time is no less than astonishing in relation to ISX4,i.e. the non-DC erythritol example 7. It is thus noted that thesalivation effect is increased a very long time after the major part ofnon-DC erythritol based tablet has been swallowed or collected duringthe measurement.

1-95. (canceled)
 96. An oral chewable tablet for delivery of activeingredients to the gastrointestinal tract comprising a population ofparticles and an active ingredient to be delivered to thegastrointestinal tract, the population of particles comprising directlycompressible (DC) and non-directly compressible (non-DC) sugar alcoholparticles, the non-DC particles providing the tablet with a plurality ofdiscrete non-DC areas, and the non-DC areas resulting in induced salivageneration upon mastication of the tablet, wherein the tablet isdesigned to be masticated directly after oral administration anddesigned to deliver the active ingredient to the gastrointestinal tractas part of the saliva generated upon mastication of the tablet.
 97. Theoral chewable tablet according to claim 96, wherein the non-DC sugaralcohol particles have not been granulated prior to tableting.
 98. Theoral chewable tablet according to claim 96, wherein the activeingredient is absorbable in the gastrointestinal tract.
 99. The oralchewable tablet according to claim 96, wherein the active ingredient isa gastrointestinal agent acting in the gastrointestinal tract.
 100. Theoral chewable tablet according to claim 96, wherein at least 50% byweight of the active ingredient is absorbed in the gastrointestinaltract.
 101. The oral chewable tablet according to claim 96, wherein theactive ingredient is a gastrointestinal stimulant.
 102. The oralchewable tablet according to claim 96, wherein the active ingredient isa gastrointestinal relaxant.
 103. The oral chewable tablet according toclaim 96, wherein the tablet comprises means for sustained release. 104.The oral chewable tablet according to claim 96, wherein the activeingredient is at least partly encapsulated.
 105. The oral chewabletablet according to claim 96, wherein the active ingredient is aprodrug.
 106. The oral chewable tablet according to claim 96, whereinthe tablet is designed to release the active ingredient in the oralcavity for absorption through the oral mucosa of a part of the activeingredient, and wherein the tablet is designed to deliver another partof the active ingredient to the gastrointestinal tract as part of salivagenerated upon mastication of the tablet.
 107. The oral chewable tabletaccording to claim 96, wherein the active ingredient is an activepharmaceutical ingredient.
 108. The oral chewable tablet according toclaim 96, wherein the active ingredient is a nutraceutical.
 109. Theoral chewable tablet according to claim 96, wherein said population ofparticles is tableted into a first module of the tablet and combinedwith a second population of particles that is tableted into a secondmodule of the tablet.
 110. The oral chewable tablet according to claim96, wherein a series of at least 10 of said tablets comprises saidnon-DC particles in an amount varying with a relative standard deviation(RSD) below 10%.
 111. (canceled)
 112. The oral chewable tablet accordingto claim 96, wherein the non-DC sugar alcohol particles are selectedfrom the group consisting of non-DC particles of erythritol, non-DCparticles of maltitol, non-DC particles of xylitol, and combinationsthereof.
 113. The oral chewable tablet according to claim 96, whereinthe non-DC sugar alcohol particles are non-DC erythritol particles. 114.The oral chewable tablet according to claim 96, wherein the tabletcomprises said non-DC sugar alcohol particles in an amount of at least10% by weight of the tablet.
 115. The oral chewable tablet according toclaim 96, wherein the tablet has a weight ratio between said non-DCsugar alcohol particles and said DC sugar alcohol particles, which isbetween 0.3 and 0.7.
 116. The oral chewable tablet according to claim96, wherein saliva generation upon mastication of the tablet is inducedcompared to a tablet where the discrete areas are based on DC sugaralcohol particles.
 117. The oral chewable tablet according to claim 96,wherein the tablet generates more than 1.5 mL saliva within 30 secondsfrom onset of mastication.
 118. An oral chewable tablet for delivery ofactive ingredients to the gastrointestinal tract comprising a populationof particles and an active ingredient to be delivered to thegastrointestinal tract, the population of particles comprising directlycompressible (DC) and non-directly compressible (non-DC) sugar alcoholparticles, wherein the entire tablet is designed to be masticated and toturn into liquid within 20 seconds of mastication.
 119. An oral chewabletablet for delivery of active ingredients to the gastrointestinal tractcomprising a population of particles and an active ingredient to bedelivered to the gastrointestinal tract, the population of particlescomprising directly compressible (DC) and non-directly compressible(non-DC) sugar alcohol particles, wherein the tablet is designed to bemasticated, including any module of the tablet, and to dissolve within20 seconds of mastication.
 120. The oral chewable tablet according toclaim 96, wherein the active ingredient is selected from alginate,atenolol, aspirin (acetylsalicylic acid), ampicillin, aminosalicylates,anhydrous citric acid, bisacodyl, bismuth subsalicylate, bupropion,caffeine, calcium, calcium carbonate, cetirizine, cimetidine, cisapride,clarithromycin, desloratadine, dexlansoprazole, diphenhydramine HCl,diphenhydramine citrate, dimenhydrinate, docusate erythromycin,dopamine, esomeprazole, famotidine, fexofenadine HCl, guaifenesin,hydrotalcite, ibuprofen, ketoprofen, lactase enzyme, lansoprazole,loratadine, lorcaserin, loperamide, loperamide HCl, magnesium, magnesiumcarbonate, magnesium hydroxide, melatonin, methamphetamine HCl,metoclopramide, metronidazole, montelukast, mycostatin, naltrexone,naproxen, naproxen sodium, nizatidine, omeprazole, ondansetrone,orlistat, pantoprazole, paracetamol (acetaminophen), pectin, phentermineHCl, polypodium leucotomos, prednisolone, prednisone, progesterone,propranolol, propantheline Currently bromide, pseudoephedrine HCl,phentermine, rabeprazole, ranitidine, roflumilast, scopoloamine butylhydroxide, simethicone, sodium, sodium bicarbonate, sodium docusate,sumatriptan, testosterone, tetracycline, topiramate, vitamin A, vitaminB, vitamin B12, vitamin C (ascorbic acid), vitamin D, and vitamin E,vitamin K, or any combination thereof.
 121. The oral chewable tabletaccording to claim 96, wherein at least 30% by weight of the non-DCsugar alcohol particles have a particle size above 500 μm.